Weight loss efficiency and safety of tirzepatide: A Systematic review

Objective Tirzeptide is a novel glucagon-like peptide-1 receptor (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) drug, which shows good efficiency for weight loss. Therefore, we aim to investigate the efficacy and safety of tirzepatide for weight loss in type 2 diabetes mellitus (T2DM) and obesity patients in this meta-analysis study. Methods Cochrane Library, PubMed, Embase, Clinical Trials, and Web of Science were searched from inception to October 5, 2022. All randomized controlled trials (RCTs) were included. The odds ratio (OR) was calculated using fixed-effects or random-effects models by Review Manager 5.3 software. Results In total, ten studies (12 reports) involving 9,873 patients were identified. A significant loss body weight in the tirzepatide group versus the placebo by -9.81 kg (95% CI (-12.09, -7.52), GLP-1 RAs by -1.05 kg (95% CI (-1.48, -0.63), and insulin by -1.93 kg (95% CI (-2.81, -1.05), respectively. In sub-analysis, the body weight of patients was significantly reduced in three tirzepatide doses (5 mg, 10 mg, and 15 mg) when compared with those of the placebo/GLP-1 RA/insulin. In terms of safety, the incidence of any adverse events and adverse events leading to study drug discontinuation was higher in the tirzepatide group, but the incidence of serious adverse events and hypoglycaemia was lower. Additionally, the gastrointestinal adverse events (including diarrhea, nausea, vomiting and decreased appetite) of tirzepatide were higher than those of placebo/basal insulin, but similar to GLP-1 RAs. Conclusion In conclusion, tirzeptide can significantly reduce the weight of T2DM and patient with obesity, and it is a potential therapeutic regimen for weight-loss, but we need to be vigilant about its gastrointestinal reaction.


Introduction
Obesity is a metabolic disease, which is related to a variety of chronic diseases in addition to affecting the quality of life [1]. Recent statistics indicate that overweight/obesity and its relentless global rise, with the number of people with excess body weight reaching > 2 billion, approximately 30% of the world population [2]. Some researchers reckon that overweight and obesity are major risk factors for cardiovascular disease [3]. Thus, weight loss can reduce the incidence of cardiovascular events and all-cause mortality in cardiovascular patients [3,4], and lessen the incidence of diabetes [5,6]. Currently, a growing number of drugs are used for weight loss, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs). Liraglutide was the first GLP-1RAs to be approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of obesity [7]. Additionally, more evidence supports the use of the GLP-1RAs semaglutide in people with obesity without type 2 diabetes mellitus (T2DM) [8].
As time goes on, an increasing number of drugs have been developed for the treatment of T2DM or obesity. In recent years, Glucagon-like peptide-1 receptor (GLP-1) and glucosedependent insulinotropic polypeptide (GIP) are known as incretins among the many hormones in the body that has attracted the attention of researchers, which can promote insulin release after meals, lowering blood sugar and making the body more sensitive to insulin [9,10]. Moreover, it also contributed to weight loss by slowing gastric emptying. GLP-1RAs are now considered the choice of injectable therapy for many people with T2DM and obesity, with several members of the class having weight loss efficacy [11][12][13]. Building on that concept, the combined GIP and GLP-1 RAs have been proposed as a novel therapeutic option for T2DM and obesity.
Tirzepatide (LY3298176, Mounjaro) is the first dual GIP and GLP-1 RAs for the treatment of T2DM, obesity, and nonalcoholic steatohepatitis [14]. It is a first-in-class GLP-1/GIP receptor agonists that FDA approved on May 13, 2022, to improve blood sugar control in adults with T2DM as an adjunct to diet and exercise [15]. Tirzepatide can lower the hemoglobin A1C level more than other medications to which it was compared [16,17]. At the same time, there is growing evidence that tirzepatide plays a role in the weight loss of T2DM patients. Furthermore, another study showed that tirzepatide did not increase the risk of major cardiovascular events in participants with T2DM versus controls [18]. Tirzepatide also supported substantial weight loss in a recent clinical trial, potentially supporting its use as an obesity treatment [19].
In this paper, we performed a comprehensive systematic review and meta-analysis of all currently available randomized controlled trials (RCTs) of tirzepatide in individuals with T2DM and obesity to evaluate weight loss and adverse events when they were treated with tirzepatide.

Study search and selection
To conduct our study, we systematically searched PubMed, EMBASE, Cochrane library, Web of Science, and Clinical Trails databases from their inception to October 5, 2022, in the English language. "Tirzepatide" [MeSH] OR "LY3298176" OR "Mounjaro" were among the search phrases used. According to the inclusion and exclusion criteria, two researchers independently read the title and abstract of the literature for preliminary screening and also read the full text of literature that potentially met the inclusion criteria. Any disagreement was discussed and decided by the third researcher.
Studies were included for this meta-analysis if they met the following criteria: only RCT; adults of obesity patients with or without T2DM; tirzepatide is the intervention drug; comparison is placebo or antidiabetic; and outcome of efficacy and safety. Authorship; year of publication; randomization; intervention; and patient number; study design; study duration; study site; study population; therapy duration; body weight; and risk of AEs were extracted from all included studies.

Outcome indicators and the risk of bias assessment
The primary outcome indicators included body weight, glycosylated hemoglobin, type A1C (HbA1c) and the incidence of any AEs. The secondary outcome indicators included the incidence of SAEs, AE leading to study drug discontinuation, hypoglycemia, and other AEs. The Cochrane Collaboration bias assessment tool was used to evaluate the risk bias of the included studies by two researchers independently [20]. According to the tool the risk was categorized as "high risk", "low risk", or "unclear". Review Manager 5.3 was used to carry out quality assessment and an investigation of publication bias.

Statistical analysis
Review Manager 5.3 was utilized to perform statistical analysis. The mean difference (MD) was used as the effect analysis statistic for continuous measurement data; Oddi ratio (OR) was used as the effect analysis statistic for dichotomous variables, and 95%CI was considered for each effect. Statistical heterogeneity between the results was analyzed by Chi-square (χ 2 ) test, and the heterogeneity was quantitatively judged by I 2 . When I 2 � 50% and P > 0.1, the fixed effect model was applied, and when I 2 > 50% and P < 0.1, the random effect model was applied. Additionally, we also investigated the source of heterogeneity with a sensitivity analysis when I 2 was higher than 50%. The meta-analysis level was set as 0.05.

Quality assessment
The results of the quality assessment of 10 studies are furnished in

Efficacy analysis
In this meta-analysis, the included 10 RCT studies displayed varying degrees of weight loss efficacy. Over all, meta-analysis showed a significant reduction in body weight in the tirzepatide group versus the placebo group by -9.81 kg (95% CI (-12.09, -7.52). There were three doses investigated compared to the placebo group were affected significantly reduced the body weight of patients  (Fig 4). The sensitivity analysis excluding the SUR-MOUNT-1 [19] trial showed that statistical heterogeneity decreased from 94% to 43%, 97% to 35%, and 96% to 78%, respectively.
The changes of HbA1c of patients was also collected. When compared with placebo, tirzepatide can significantly reduce the HbA1c of patients [5 mg: MD = -1.55%, 95% CI (-1.

Safety analysis
For the safety, meta-analysis showed a significant difference the incidence of any adverse events between tirzepatide group and placebo group [OR = 1.59, 95% CI (1.29, 1.95), P < 0.00001, I 2 = 53%], GLP-1 RAs group [OR = 1.15, 95% CI (1.00, 1.32), P = 0.05, I 2 = 0%], and basal insulin [OR = 1.55, 95% CI (1.25, 1.91), P < 0.0001, I 2 = 69%], respectively. In the sub-analysis, the incidence of any adverse events was lower in the tirzepatide group than in the placebo group and basal insulin. But when compared to GLP-1 RAs, there was no significant difference in the tirzepatide 5 mg [OR = 1.01, 95% CI (0.80, 1.28), P = 0.92] and 10mg [OR = 1.17, 95% CI (0.92, 1.48), P = 0.2] groups (Table 3). Additionally, there was a statistically significant difference in the incidence of adverse events leading to study drug discontinuation between tirzepatide and placebo, between tirzepatide (15mg) and GLP-1 RAs, and between tirzepatide (5mg) and basal insulin. However, no significant statistics were found between tirzepatide and GLP-1 RAs (5mg and 10 mg) or between tirzepatide (10mg and 15 mg) and basal insulin.  In this study, there was no significant difference in the incidence of serious adverse events between tirzepatide and placebo, and basal insulin, but significant difference to GLP-1 RAs. Hypoglycemia is the major SAEs, hypoglycemia definition as blood glucose < 70 mg/dL. Across all trials, the hypoglycemia risk of tirzepatide did not differ compared with placebo and GLP-1 RAs, and was lower with tirzepatide compared with basal insulin.
After consuming tirzepatide, most of the patients experienced diarrhea, nausea, vomiting, decreased appetite, constipation, injection site reactions, and nasopharyngitis. Compared with basal insulin and placebo, more frequent gastrointestinal adverse events occurred, including diarrhea, nausea, vomiting, decreased appetite, and constipation in all tirzepatide groups. When compared with the GLP-1 RAs, the tirzepatide group showed a similar risk of nausea, diarrhea, vomiting, and constipation. While tirzepatide 5 mg and 10 mg were also associated with a higher incidence of decreased appetite. Meanwhile, there were no statistically significant differences in the incidence of injection site reactions between tirzepatide and GLP-1 RAs, and basal insulin. When compared with placebo, the incidence of injection site reactions was lower in tirzepatide (5 mg and 10 mg), but no significant difference in tirzepatide (15 mg). Besides, there was no significant difference in the incidence of nasopharyngitis was noticed between tirzepatide and placebo, GLP-1 RAs, and basal insulin.

Discussions
Tirzepatide as the first dual GIP and GLP-1 RA drug, which shown effects on hypoglycemia, body weight and cardiovascular indicators in previous studies [31][32][33]. Its effect on body weight could make it useful as a weight loss drug. Thus, in this meta-analysis, a systematic review to assess the weight loss efficacy and safety of tirzepatide is conducted. Based on our

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findings, both doses of tirzepatide (5 mg, 10 mg and 15 mg) were more effective than other drugs in reducing body weight.
With the increase of obese people, the drugs for obesity treatment has been on the rise, and most of the drugs currently used to treat obesity started out as treatments for diabetes [34]. Based on our findings, both doses of tirzepatide were more effective in reducing bodyweight compared with other drugs. In this study, we included 10 RCT (12 reports) and compared the weight loss effects of tirzepatide with placebo, insulin, and GLP-1 RAs. The results showed that tirzepatide could reduce the weight of T2DM and obese patients. This is the same as the previous study showed [32,35]. At the same time, the network meta-analysis results of Alkhezi et al. also showed that compared with liragrutide and semaglutide, tirzepatide had better weight reduction in non-diabetes patients, and the safety results were similar without difference [36]. Furthermore, some studies found that meaningful weight loss is achieve 5~10% [37]. In our study, tirzepatide were more effective than other drugs in reducing bodyweight of 5%, 10%, or 15%. More importantly, compared with placebo, GLP-1 RAs and insulin, tirzepatide can significantly reduce their HbA1c level of patients, and the results were same with other studies [32,38].
For the safety, a significant difference the incidence of any adverse events between tirzepatide group and placebo/GLP-1 RAs/basal insulin. This is contrary to the results of a study by Bhagavathula et al. the results shown that no significant difference the incidence of any adverse events [32]. In addition, no significant difference in the incidence of SAEs between tirzepatide and placebo, and basal insulin, but significant difference to GLP-1 RAs. Across all trials, the risk of hypoglycemia with tirzepatide did not differ compared to placebo and GLP-1 RAs, but was lower with tirzepatide than with basal insulin. In the same results has been found in the study by Karagiannis et al. that incidence of serious adverse events did not differ between any of the tirzepatide doses and any comparator [35].
Gastrointestinal adverse events were the most common adverse events in all groups. In this study, the incidence of gastrointestinal adverse events, including diarrhea, nausea, vomiting, and decreased appetite, and the incidence of diarrhea, nausea, vomiting, and constipation were similar when comparing tirzepatide with GLP-1 RAs. However, in comparison with placebo or basal insulin, tirzepatide increased the odds of diarrhea, nausea, vomiting, decreased appetite, and constipation. The results were the same as this study [35]. The clinical trials of SURPASS reported on the gastrointestinal system, and nausea, diarrhea and vomiting were the most common AEs [17]. The results from other studies found that GLP-1 receptor agonists are often accompanied by nausea, emesis, and undesired anorexia. Importantly, the hypophagic and emetic effects of GLP-1 receptor agonists are caused by activation of central GLP-1 receptors [39]. Gastrointestinal side effects of high-dose GLP-1 RAs and co-agonists occurred in 30%~70% of patients, mostly arising within the first 2 weeks of the first dose, being mild or moderate in severity, and transient [40]. A study found the incidence of gastrointestinal bleeding occurred most frequently 0~4 weeks after the first dose and was higher for the 15 mg tirzepatide group [41]. In addition, all the included studies were RCT, and some studies have a high bias risk for research because they did not have detailed randomization methods and allocation concealment or open-label. Of these, this may affect the positive outcomes. Moreover, this study could have a higher effect on weight loss due to participants of the SURMOUNT-1 study not having T2DM and the SURPASS J-Combo study with only Japanese populations. Sensitive analysis results showed that statistical heterogeneity was decreased after removing the SURMOUNT-1 study and the SURPASS J-Combo study, but the statistical effect did not change.
There are limitations in the current study. First, as all the RCTs involved the pharmaceutical industry, the positive outcomes should be interpreted cautiously [42,43]. Second, only one study focused on the obesity patients in all 10 RCTs (12 reports), and RCTs have generally carried out in selected populations of T2DM or obesity patients. More research is suggested in the available guidance. Fortunately, 20 additional trials [17,44,45] aiming to investigate the   efficacy of tirzepatide in the clinical setting of T2DM or obesity are ongoing. We can obtain more data to analyze after these trials are completed in the near future.

Conclusion
To sum up, this meta-analysis indicated that tirzepatide could significantly decrease body weight in T2DM and obesity patients, and it is a potential therapeutic regimen for weight-loss, but we need to be vigilant about its gastrointestinal reaction.
Supporting information S1